Chapter 4: NeuroimmunologyA Connection with the Brain

Immunology and neuroscience may well be the two most complex ﬁelds of biomedical research today. Neuroimmunology, the study of the interaction between our central nervous system (the brain and spinal cord) and our immune system, melds these two disciplines.

Although questions about how your immune cells affect the brain and how your brain inﬂuences immune function are not new, neuroimmunology as a ﬁeld of research is relatively young. The term has been in use only since the 1960s, and it was just 30 years ago that a neuroimmunology branch was established at the National Institutes of Health, the federal agency responsible for advancing biomedical research. Today the study of nervous system–immune system interactions is thriving, as more and more scientists from diverse areas of medical research are drawn into the ﬁeld.

Immune Privileged

Scientists have long understood that the brain, with its complex pathways of nerve connections developed over a lifetime of experiences, holds special status regarding how the immune system defends it. This “immune privilege” may be the brain’s way of protecting its delicate tissue from potential damage by immune cells in their rush to eliminate a threat.

A computer simulation shows the primary nerve pathways in the body. The brain and the spinal cord make up the central nervous system. Nerves extend from the spinal cord to every part of the body, forming the peripheral nervous system. Pasieka / Science Photo Library

In their normal response, immune cells release biochemicals that neutralize foreign particles and signal other components of the immune system to react to the threat. Some of these chemicals are toxic to nerve cells and can damage or kill them, disrupting brain function. Inﬂammation, another weapon the immune system uses to eliminate its enemies, can quickly spiral out of control in the central nervous system and cause secondary damage beyond the original injury or infection. This is a particular problem with stroke or severe head injury, for example, and researchers are searching for ways to shut down this “inﬂammatory cascade.”

By Invitation Only

One of the ways the immune system treats the brain differently is evident in the activity of B lymphocytes, the immune cells that patrol the body on the lookout for trouble and that mount an immediate attack if any is found. B cells do not freely enter the brain as they do most other organs but migrate there only after an immune response has been activated elsewhere in the body. It’s as if the brain has locked its doorways to these immune cells, allowing them to enter only by special invitation, a process scientists do not yet fully understand. The blood-brain barrier, a ﬁne mesh in the walls of the brain’s blood vessels that prevents larger molecules in the blood from entering the brain, normally keeps immune cells, including B cells, at bay.

The brain even has its own exclusive army of sentinels, called microglia. These tiny cells can be thought of as highly trained specialists within the immune defense system, having evolved with the sole purpose of protecting the sensitive tissue of the brain without perturbing its complex nerve-cell connections and pathways. Microglia respond swiftly to an assault on the brain, sometimes migrating great distances to reach the battleﬁeld, and wall off offending microbes or areas that have been damaged by disease or injury. Still, even microglia can spell trouble for delicate brain tissues, and scientists are trying to understand how their response to sites of injury or infection might itself cause damage to neural structures.

Brain Tumor

Tumors have many ways to interfere with or evade the immune system. Tumors that form in the brain are especially difﬁcult to treat. The blood-brain barrier, in its role as guardian, prohibits certain cancer treatments from reaching the brain. However, some experimental therapies are showing promise.

One method involves extracting brain tumor cells from a patient and using them as a vaccine to produce T cells in the patient’s lymph nodes. Researchers who developed this method then removed the T cells, multiplied them, and injected them back into the patient. Initial results were encouraging, but it is difﬁcult to harvest tumor cells from every patient, and the technique is being reﬁned.

Another treatment now being developed employs dendritic cells to “train” T cells, including enabling them to enter the brain. The process begins with presenting tumor cells to the dendritic cells, which are the body’s natural system for initiating immunity. The dendritic cells, which present tumor antigens on their surfaces that activate T cells and express a number of other immune-stimulating functions, are then returned to the immune system to stimulate it to recognize and attack the tumor.

Yet another possibility lies with binding a toxin to individual immune system molecules, which can dock with the receptors on tumor cells, then get inside and work to kill the tumor cells. Researchers are now testing the effectiveness of this treatment. In the end, a combination of approaches may be necessary because of brain tumors’ shrewd ability to counter the defenses of the immune system.

Dual Roles for Some Immune Components

Scientists are learning that in addition to microglia, other components of the immune system play previously unrecognized roles in the nervous system. For example, Carla Shatz and her colleagues at Harvard University recently discovered that genes for a family of immune-system molecules that were not thought to be present in the central nervous system are actually expressed throughout the brain. Major histocompatibility complex (MHC) molecules enable the immune system to identify cells as friends or foes. The researchers bred mice in which the genes that specify the genetic code for MHC molecules were “knocked out.” Without these molecules, nerve cell function was impaired.

From these and other experiments, Shatz and her colleagues found that MHC molecules play an essential role in brain development, enabling brain cells to determine which other brain cells to connect to as the brain “wires up.” This suggests that the same molecules that are fundamental to disease recognition in immunity also play a role in the developing brain. Other molecules are also common to both systems, and scientists are following up on a number of lines of research to better understand how the immune and nervous systems inﬂuence each other.

Synergy in Synapses

Nerve cells communicate with one another by forming synapses, junctures where nerve signals are transmitted when chemical messengers from one neuron interact with specialized molecules on another. Immunologists have recently discovered that immune cells also use synapses to communicate.

As part of the body’s immune response, dendritic cells present invading antigens to T cells. The T cells gather information from the antigen and produce antibodies that prevent future infection by the same antigen. Benjamin Reese

Researchers at New York University have used high-powered laser microscopes (“two photon microscopy”) to spy on this process. They inject ﬂuorescent dyes into the immune cells of laboratory animals and then examine the cells during an immune reaction. The investigators have watched, in real time, as an antigen-presenting cell, such as a dendritic cell, locks onto specialized receptors on the surface of a T cell to form a molecular bridge, as if convening a strategy session to plan their defense. Once connected, the antigen-presenting cell sends chemical signals, just as nerve cells do, that order the T cell to activate and tell it what kind of enemy it is facing.

In addition, immune synapses rely on many of the same molecules as nerve synapses. But, unlike nerve synapses, which can be stable and last even a lifetime, immune synapses are transient and dynamic, forming as necessary to mount an immune response and lasting only until the job is done. The communication between immune cells is also somewhat slower than that between nerve cells, occurring over a period of seconds to minutes compared with the millisecond timing of nerve transmission.

Roles in Neurological Disease

One of the most pressing challenges facing neuroimmunology is to understand how the immune system is involved in neurological disease. The nervous system is affected in some autoimmune diseases, which occur when the immune system mistakenly attacks the body’s own tissue (as described in Chapter 1). In multiple sclerosis, for example, immune cells target myelin, the fatty sheath that surrounds nerve ﬁbers and enhances nerve transmission. Many scientists believe that this attack may be triggered by a viral infection, that immune cells responding to the virus confuse myelin tissue with the real enemy. Some forms of childhood epilepsy and encephalitis (brain inﬂammation) are believed to have an autoimmune component, as are a group of childhood neuropsychiatric disorders associated with streptococcal infection.

Scientists are just beginning to understand what role the immune system may play in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. Scientiﬁc interest in any possible immune connection to degeneration exploded after it was found that injecting mice that had a form of Alzheimer’s disease with bits of amyloid (the brain protein that abnormally accumulates in Alzheimer’s) effectively decreased formation of the amyloid plaques that interfere with nerve cell communication as the disease progresses. Researchers are now testing various immune therapies against Alzheimer’s and are trying to sort out precisely how—or if—the immune system inﬂuences the formation of the plaques that are a central feature of this fatal condition.

A scan of a brain with Alzheimer’s disease, left, shows how it has degenerated compared with a healthy brain. Pasieka / Photo Researchers, Inc.

The ultimate goal of such research is to develop better treatments for devastating neurological conditions. While many questions remain to be answered, the inﬂux of scientiﬁc minds into the study of neuroimmunology has already fueled tremendous progress and given hope to the millions of people who suffer from diseases of the brain and nervous system.